FUNCTIONAL-CHARACTERIZATION OF THE MUSCARINIC RECEPTOR IN RAT LUNGS

The effects of various muscarinic antagonists on antigen- and acetylcholine-induced bronchoconstriction were studied. In isolated and ventilated lungs of naive rats, the pA2 values with respect to acetylcholine-induced bronchoconstriction were 9.01 (atropine), 8.39 (ipratropium bromide), 7.39 (pirenzepine), 5.94 (AF-DX 116, a M2-selective muscarinic antagonist), 6.91 (UH-AH 37, a novel muscarinic antagonist) and 9.37 (4-DAMP: 4-diphenylacetoxy-N-methylpiperidine methobromide). Except for ipratropium bromide, the slopes of the Schild plots were not significantly different from unity. None of the drugs were potent or effective in inhibiting bronchoconstriction or histamine release evoked by antigen challenge in actively sensitized rats. However, in vivo, in anesthetized spontaneously breathing rats, vagotomy and atropine (1 mg/kg) did reduce antigen-induced bronchoconstriction. It is concluded that functional muscarinic receptors in isolated rat lungs are probably of the M3 receptor subtype. With respect to antigen-induced bronchoconstriction and mediator release in a denervated model such as the isolated lung, they are of little, if any, importance. In vivo, vagotomy and atropine reduced antigen-induced bronchoconstriction, probably by blockade of a vagal reflex which is thought to play a role in antigen-evoked bronchoconstriction.